Life span can be extended in many animals when reproduction is repressed, but little is known about the mechanisms of this action. Evidence from the nematode C. elegans suggests that the somatic gonad can produce a signal to ensure longevity, and signals from the germ lineage produce counterbalancing signals that accelerate aging. The identity and operation of these signals are unknown. With Drosophila melanogaster we propose to understand the function of these aging regulatory systems. In our preliminary work we find that loss of germline stem cells from the mature adult gonad, but not the primordial gonad, is sufficient to extend both male and female lifespan. We shall use these differences in the timing of GSC loss to identify cells and molecular signals of the somatic gonad required to induce longevity assurance. Our preliminary work identifies the JAK/STAT and TGF2 families as candidates for the cell-to-cell signaling that is up-regulated when loss of GSC extends lifespan. Research in this proposal will establish whether and how these signals play a functional role in the control of aging. Furthermore, while these signals may affect aging, they are likely to do so indirectly by affecting the function of systemically circulating hormones. Since insulin/IGF signaling is thought to be required for GSC loss to extend lifespan in C. elegans, we assessed the state of insulin signaling when GSC loss extends Drosophila lifespan. Given that reduced insulin signaling is known to increase Drosophila survival, we anticipated there would be fewer messages for insulin- like peptides in these flies. Unexpectedly, we found insulin-like message was several fold increased in long-lived adults. To explain this paradox we propose that GSC loss extends lifespan because the somatic gonad produces signals that repress the insulin sensitivity of tissues in the somatic body, and active GSC suppress this signal. Further preliminary data are consistent with this model of `insulin impedance': transcriptional targets of dFOXO are elevated in flies without germline, and these flies strongly express an insulin inhibitory IGF-like binding protein, Imp-L2. Studies in this proposal will robustly test this hypothesis and establish specific molecular mechanisms by which reproduction modulates animal aging. PUBLIC HEALTH RELEVANCE: Reproductive investment accelerates aging in animals ranging from nematodes, to insects, to mammals and including humans. Understanding the cellular and molecular mechanisms underlying this nearly universal mode of aging control will provide fundamental insights on how human aging is affected by the hormone systems controlled by reproduction. This proposal works with the fly Drosophila melanogaster to explore the effects of reproduction upon candidate aging regulatory hormone systems that are common to insects and mammals.